AT400845B - NEW THIENOTHIAZINE DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND THEIR USE - Google Patents

Description

AT 400 845 B

The invention relates to new thienothiazine derivatives, a process for their preparation and their use.

No. 4,180,662 discloses thienothiazine derivatives which are unsubstituted on the pyridine nucleus. These compounds have good cyclooxygenase inhibition. 5 Also known from Chemical Abstracts, Volume 111, No. 19, 166771 n and Chemical Abstracts, Volume 115, No. 3, 21532 h thienothiazine derivatives which are unsubstituted on the pyridine nucleus or substituted by a hydroxyl group. These compounds also have good cyclooxygenase inhibition.

It was now possible to find new thienothiazine derivatives substituted on the pyridine nucleus which, with the cyclooxygenase inhibition largely retained, bring about a significantly increased inhibition of the 5-lipoxy-10 genes.

The invention accordingly relates to thienothiazine derivatives of the formula I 75 20

OH 0) in which R is a mono- or polycyclic, optionally partially hydrogenated 5-12-membered aryl or 25 heteroaryl radical, which can optionally be substituted one or more times by halogen, lower alkyl or lower alkoxy, A is halogen and B is halogen , as well as their pharmaceutically acceptable salts.

Preferred compounds are those in which the substituent is linked at the 6-position of the pyridine. 30 In formula (I), R is a mono- or polycyclic, optionally partially hydrogenated, 5-12-membered aryl or heteroaryl radical. These are 5-12-membered, optionally partially hydrogenated aromatic or heteroaromatic radicals, for example a phenyl, a thienyl, a furyl, a pyrrolyl, a pyrimidyl, a pyranyl, a thiadiazinyl, an azepinyl or a benzofuryl, a quinolinyl or a benzothienyl radical. These radicals can optionally be substituted one or more times by halogen, for example F, CI, Br or by lower alkyl or lower alkoxy.

Lower alkyl means a straight-chain or branched alkyl radical with 1-4 C atoms, for example a methyl, an ethyl, a propyl, an i-propyl radical, a butyl radical, an i-butyl radical or a t-butyl radical. 40 Niederaikoxy means a straight-chain or branched alkoxy radical with 1-4 C atoms, for example methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy or t-butoxy.

Preferred compounds are those in which R denotes a phenyl, a benzofuryl or a quinolinyl residue which may be halogenated one or more times. A can be halogen, for example CI, F, Br. 45 B means halogen, for example CI, F or Br.

Another object of the invention is a process for the preparation of compounds of formula (I), which is characterized in that a compound of formula (II) o

OH 50 2 55

AT 400 845 B in which Fh is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and A and B have the meaning given above, with a compound of the formula (III)

in which R has the meaning given above, and the compounds of the formula (I) thus obtained are optionally converted into their pharmaceutically acceptable salts.

The compounds of the formulas II and III are known from the literature or can be prepared analogously to them by customary methods known to the person skilled in the art.

The process according to the invention can preferably be carried out in one of the following ways: a) dissolving a compound of the formula II in an inert solvent, such as diethyl ether, dioxane, toluene, benzene or the like, and at a temperature of from -20 ° C to 100 * C adds one equivalent of a strong base, such as butyllithium or LDA, in an inert solvent, for example n-hexane, optionally under inert gas, adds 1-10 equivalents of a compound of the formula III to this salt solution, adds at least 1 equivalent of the strong base and between 0.5 and 60 hours, preferably 1-48 hours at -20 ° C to 100'C, or b) the compounds of the formula II and the formula III in an inert high-boiling solvent, such as toluene, xylene, pyridine, Quinoline, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide dissolves and this mixture is heated to 100 ° C. to 200 ° C. for 1-30 hours.

The compounds of formula I thus obtained can optionally be easily purified, for example by recrystallization.

The compounds of general formula I are acidic compounds and can be converted into their pharmaceutically usable salts in a conventional manner using inorganic or organic bases.

Salt formation can be carried out, for example, by reacting the compounds of formula I in a suitable solvent, e.g. Dissolves water, a lower aliphatic alcohol, for example methanol, ethanol and the like, in tetrahydrofuran, dioxane, benzene, diethyl ether, dimethylformamide or dimethyl sulfoxide, adds an equivalent amount of the desired base and, after the salt formation has ended, the solvent is distilled off under vacuum.

If necessary, the salts can be further purified after their isolation, for example by recrystallization.

Examples of suitable pharmaceutically acceptable salts are metal salts, in particular alkali metal salts and alkaline earth metal salts, such as sodium, magnesium, potassium or calcium salts. Other pharmaceutically usable salts are easily crystallizable ammonium salt, which are derived from ammonia or organic amines, such as, for example, mono-, di- or tri- (lower alkyl, cycloalkyl- or hydroxyalkyl-) amines, lower alkylenediamines, (hydroxy-lower alkyl) - or (aryl -Lower alkyl) - Lower alkylammonium bases, for example methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane, benzyltrimethylammonium hydroxide and the like.

The compounds of the formula I and their salts according to the invention are orally active and show, compared to compounds unsubstituted on the pyridine nucleus, such as, for example, the 6-chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H known from US Pat. No. 4,180,662 -thieno [2,3-e] 1,2-thiazine-3-carboxamide-1,1-dioxide (" Lornoxicam ") surprisingly shows a significantly higher inhibition of 5-lipoxygenase, the cyclooxygenase inhibition being largely retained.

They are therefore used to treat complaints caused by the natural 5-lipoxygenase product, namely leukotriene-B *, such as Inflammation and pain in allergic asthma, arthritis, skin allergy, etc. are particularly suitable.

On the basis of these pharmacological properties, the new compounds can be used alone or in a mixture with other active substances in the form of conventional pharmaceutical preparations as medicaments for the treatment of diseases which can be cured or alleviated by inhibiting 5-lipoxygenase. 3rd

AT 400 845 B

The invention further relates to medicinal products which are used, for example, in the form of pharmaceutical preparations which contain the compounds of the formula (I) according to the invention or their salts which can be used for pharmaceutical purposes in a mixture with a pharmaceutical, organic or inorganic carrier material suitable for oral, enteral, parenteral or topical application , for example water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and the like.

The pharmaceutical preparations can be in solid form, for example as tablets, film-coated tablets, coated tablets, suppositories, capsules, microcapsules, or in liquid form, for example as solutions, injection solutions, suspensions or emulsions or in compositions with delayed release of the active ingredient,

If necessary, they can be sterilized and / or they contain auxiliaries, such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers.

In particular, pharmaceutical preparations can contain the compounds according to the invention in combination with other therapeutically valuable substances. These can be used to formulate the compounds according to the invention in combination with the abovementioned auxiliaries and / or excipients to give combination preparations.

The new compounds can be present in the compositions according to the invention in a proportion of 4-200 mg per tablet, the rest being a pharmaceutically acceptable filler.

A suitable dose for administering the compounds is approximately 4-200 mg / kg per day, but other doses may also be considered depending on the condition of the patient to be treated. The new compounds can be administered in multiple doses and orally.

Example 1: N- [6- (2-Benzo [b] furyl) -2-pyridiny] -6,7-dichloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] [1 , 2] thiazine-3-carboxamide-1,1-dioxide 428 mg (2.03 mmol) 6- (2-benzo [b] furyl) -2-pyridinamine and 700 mg (3.99 mmol) 6.7- Dichloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] [1,2] thiazine-3-carboxylic acid methyl ester-1,1-dioxide are in 7 ml abs. Xylene heated to boiling for 9 hours. The solution is cooled, diluted with 25 ml of diethyl ether, the precipitate is filtered off and digested several times with cold diethyl ether. This crude product is recrystallized from chloroform / activated carbon.

Yield: 734 mg of yellow crystals (57% of th.)

Mp .: 225-227'C thin layer chromatogram: PE: EtOH = 2: 1 RF = 0.25 1H-NMR: (DMSO) 5 (ppm): 8.09-7.88 (m, 2H, Py-H5, Bzfu-H7); 7.74-7.53 (m, 4H, Bzfu-H3.4, Py-H3.4); 7.43-7.21 (m, 2H, Bzfu-H5.6); 3.02 (s, 3H, CH3)

Example A:

The formation of prostaglandin D2 by neutrophils was used as a measure of the cyclooxygenase activity and the formation of leukotriene B4 as a measure of the 5-lipoxygenase activity. Male Sprague Dawley rats (250-300 g) were injected with lamda-carrageenan 1 mg intraperitoneally (dissolved in 0.5 ml distilled water).

After 16 hours, the rats were sacrificed by exposure to diethyl ether. 15 ml ice-cold Hanks balanced salt solution (HBSS) were i.p. injected, the neutrophils harvested by suction (10 ml), centrifuged (5 min, 100 g, 4-C), the supernatant solution decanted and the cells resuspended in HBSS at 4 “C to a concentration of 5x106 cells / ml. 400 ul cell suspension (2x1ο6 cells), 0.5 ul compound dissolved in DMSO and 49.5 ul HBSS were incubated for 5 min at 37 * C. Then 50 ul A23187 (2umol / l final concentration) were added and then again incubated for 5 min at 37 ° C.

The reaction was stopped by centrifugation 10000 g, 3s and the supernatant liquid was transferred to pre-cooled plastic tubes and max. In an ice bath before starting the radioimmunoassay measurement. Leave for 1 h. PGD2 and LTB4 were measured after dilution with HBSS using commercial RIA kits.

6-Chloro-4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno (2,3-e), 1,2-thiazine-3car-boxamide-1,1-dioxide (" Lornoxicam ", Vbg.A) 4

Claims (8)

AT 400 845 B Vbg IC50 (nmol / l) PGD2 LTB4 A 0.02 > 10 1 0.036 1.3 Claims 1. Thienothiazine derivatives of the formula I in which R is a mono- or polycyclic, optionally partially hydrogenated 5-12-membered aryl or heteroaryl radical, which can optionally be substituted one or more times by halogen, lower alkyl or lower alkoxy, A is halogen and B is halogen, and their pharmaceutically acceptable salts. 2. Thienothiazine derivatives of the formula (I) according to Claim 1, characterized in that the substituent is linked in the 6-position to the pyridine. 3. N- [6- (2-Benzp [b] furyl) -2-pyridinyl] -6,7-dichloro-4-hydroxy-2-methyl-2H-thieno- [2,3-e] [1, 2] thiazine-3-carboxamide-1,1-dioxide 4. Process for the preparation of compounds of formula (I) in which R is a mono- or polycyclic, optionally partially hydrogenated 5-12-membered aryl or heteroaryl radical which may optionally be substituted one or more times by halogen, lower alkyl or lower alkoxy, A is halogen and B is halogen, characterized in that a compound of the formula (II) 5 (II) AT 400 845 BA OR. z OH in which R2 is a straight-chain or branched alkyl group with 1-4 C atoms and A and B have the meaning given above, with a compound of the formula (III) (III) in which R has the meaning given above, and the compounds of the formula (I) thus obtained are optionally converted into their pharmaceutically acceptable salts. 5. The method according to claim 4, characterized in that the reaction is carried out in the presence of a strong base. 6. Pharmaceutical preparations containing compounds of general formula (I) according to claim 1, and their salts in combination with conventional pharmaceutical auxiliaries and / or carriers. 7. Pharmaceutical preparations according to claim 6 in combination with other therapeutically valuable compounds and auxiliaries and / or carriers. 8. Compounds according to claim 1 for use as active ingredients for medicaments for the treatment of inflammation and pain. 6